Protection against future intracranial hemorrhage (ICH) is the primary reason to intervene surgically in patients harboring brain arteriovenous malformations (AVMs). Quantification of the competing risks of natural history and surgical treatment are needed to optimally inform safe and effective management. Our work in the last funding period identified genetic markers for spontaneous AVM ICH and has helped focus attention on the balance between treatment-related risks and those derived from leaving AVMs untreated. An important challenge and knowledge gap remains in how to best identify those patients who might benefit from surgical intervention, especially among those presenting with an unruptured AVM. Our preliminary data point to genetic risk markers for injury. The genes implicated act in inflammatory pathways, suggesting, for the first time, that there are commonalities between AVM risk and several other types of vascular disease. This project will provide needed biomarkers for risk assessment, and in so doing, help identify areas for parallel mechanistic studies. We propose the following specific aims: Aim 1 will identify genetic markers that predict adverse outcome in AVM patients. In unruptured AVMs, Tumor Necrosis Factor-alpha (TNF-1) and Apolipoprotein-E (APOE) genotypes will predict risk of new hemorrhage in the untreated course. Further, Tumor Necrosis Factor-alpha (TNF-1) and Activin-like Kinase-1 (ALK-1) genotypes will predict functional decline after first (presenting) AVM hemorrhage. Aim 2 examines Race- ethnicity influences on AVM hemorrhage risk, and we will show that Hispanics are at increased risk for AVM hemorrhage in the untreated course. We will evaluate race-ethnicity differences in time to new hemorrhage using self-report as well as genetic ancestry proportions determined by unlinked genetic markers, a novel application in cerebrovascular disease. Secondary analyses will include development of genetic markers to extend these methods to other racial/ethnic groups and to adjust for potential confounding. Aim 3 will use Genome-wide Association Analysis (GWA) to identify novel genetic predictors of AVM hemorrhage using Affymetrix 500K GeneChip and further fine map significant regions to identify novel candidate genes associated with AVM hemorrhage. PUBLIC HEALTH RELEVANCE: Brain arteriovenous malformations (AVMs) are an important cause of hemorrhagic stroke in young adults. Although surgical therapy can be curative, there are high costs and inherent morbidity and mortality associated with treatment that may outweigh the benefits, especially for patients with unruptured lesions. This project can provide biomarkers for risk stratification to aid rational choice of therapy to maximize benefit and minimize risk.